Cephalosporin sulfoxides are widely used intermediates in the synthesis of cephalosporin antibiotics. For example, cephalosporin sulfoxides are useful in the overall process for converting 3-methyl-3-cephem(desacetoxycephalosporins) compounds to 3-substituted-methyl-3-cephem antibiotic compounds. This functionalization of 3-methyl-3-cephem compounds proceeds via the isomerization of the 3-methyl-3-cephem to a 3-methyl-2-cephem, functionalization of the activated 3-methyl group of the 2-cephem compound, for example, with bromine, followed by oxidation of the 3-substituted-methyl-2-cephem compound to the sulfoxide. Oxidation to the sulfoxide causes the isomerization of the 2-cephem to the 3-cephem product. The isomerization of 3-halomethyl-2-cephem compounds to the corresponding 3-halomethyl-3-cephem compounds is described by Murphy in U.S. Pat. No. 3,647,786, and by Webber in U.S. Pat. Nos. 3,766,177, 3,637,678, and 3,708,479.
Additional examples of uses of cephalosporin sulfoxides are the N-deformylation procedure of 7-.beta.-formamido-3-halomethyl-3-cephem sulfoxides described by Humber in U.S. Pat. No. 3,716,533, the 3-formyl-3-cephem sulfoxides described by Webber in U.S. Pat. No. 3,674,784 and the 7-(D-2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-1-imidazolidinyl)-3-bromomethyl -3-cephem-4-carboxylic acid sulfoxides described by Chaney et al. in U.S. Pat. No. 3,767,655.
Still further examples of the use of cephalosporin sulfoxides in the synthesis of cephalosporin antibiotics are the 7-acylamido-2-spirocyclopropyl cephalosporin sulfoxides described by Spry in U.S. Pat. No. 3,843,640, the 2-methylene and 2-methyl substituted cephalosporin sulfoxides described by Wright in U.S. Pat. No. 3,660,396 and the tricyclic cephalosporin sulfoxides described by Spry in U.S. Pat. No. 3,907,785. The preparation of 3-exomethylenecepham sulfoxides via azetidinone sulfinyl chlorides and Lewis acid type Friedel-Crafts catalyst is described by Kukolja in U.S. Pat. No. 4,052,387. These 3-exomethylenecepham sulfoxides are useful intermediates in the preparation of the 3-halo substituted cephalosporins described by Chauvette in U.S. Pat. No. 3,925,372 and in the synthesis of 3-methoxy-3-cephem antibiotic compounds described by Chauvette in U.S. Pat. Nos. 3,917,587 and 3,917,588. For example, an ester of a 3-exomethylenecepham sulfoxide is reduced to the corresponding 3-exomethylenecepham ester, the ester is then reacted with ozone to form the corresponding 3-hydroxy-3-cephem ester, and the 3-hydroxy ester is reacted with phosphorous trichloride to form the corresponding 3-chloro-3-cephem ester. Alternatively, the 3-hydroxy ester is reacted with diazomethane to form the corresponding 3-methoxy-3-cephem ester. Deesterification of the 3-halo and 3-methoxyesters, affords corresponding 3-halo or 3-methoxy-substituted antibiotic acid.
As noted above, cephalosporin sulfoxides are generally useful in the synthesis of cephalosporin antibiotics. Following the completion of the reactions or synthetic procedures employing the sulfoxide form of a cephalosporin, the sulfoxide function is reduced to provide the cephalosporin molecule in the reduced or sulfide state.
Prior to this invention one preferred method for reducing cephalosporin sulfoxides was that of Murphy et al., U.S. Pat. No. 3,641,014. According to this method, cephalosporin sulfoxides are reduced with (1) hydrogen and a hydrogenation catalyst, (2) stannous, ferrous, cuprous, or manganous cations, (3) dithionite, iodide, or ferrocyanide, (4) trivalent phosphorous compounds, (5) halosilanes or (6) chloromethylene iminium chlorides wherein certain of these reducing agents require the use of an activator such as acetyl chloride or phosphorous trichloride. For example, sodium dithionate is activated with acetyl chloride in the reduction. Another method for the reduction of cephalosporin sulfoxides was disclosed by Hatfield in U.S. Pat. No. 4,044,002 which describe the reduction of cephalosporin sulfoxides using acyl bromides in the presence of bromine scavengers. More recently Kukolja and Spry described the reduction/chlorination of 3-hydroxycephem sulfoxides using phosphorous trichloride, phosphorous pentachloride or phosgene in the presence of dimethylformamide.
In view of the usefulness of cephalosporin sulfoxides in the synthesis of cephalosporin antibiotics, more efficient and more economical methods for sulfoxide reduction, have been the object of extensive research efforts. It is an object of this invention to provide a process for the reduction of cephalosporin sulfoxides. More particularly this invention is directed to a process for reducing cephalosporin sulfoxides using a recently discovered class of triaryl phosphite-halogen compounds, derived from the kinetically controlled reaction of equivalent amounts of triaryl phosphites and chlorine or bromine. The triaryl phosphite-halogen reducing compounds employed the present reduction process are useful for effecting other desirable chemical modifications (halogenation) of cephalosporin compounds. It is therefore another object of the present invention to provide processes for one step reduction/halogenation conversions of C-7 acylamino cephalosporin sulfoxides to 7-amino cephalosporins or depending on the the cephalosporin starting materials and the amounts of reagents employed C-7 acylamino halogenated cephalosporins or C-7 amino halogenated cephalosporins.